It was another exciting day of virtual sessions at #AHA20, led by intriguing findings from a few late-breaking trials!
First, the STRENGTH and OMEMI trials added nuance to ongoing discussions about the cardiovascular benefits of fish oils and cardiovascular risk reduction. The REDUCE-IT trial, published in the New England Journal of Medicine (NEJM) in 2019, showed that the highly purified fish oil icosapent ethyl improved cardiovascular outcomes in high-risk participants who had elevated triglycerides despite statin therapy. The STRENGTH and OMEMI trial, however, may temper enthusiasm about the use of fish oils in high-risk patients.
The STRENGTH trial randomized 13,000 participants in 22 countries to an omega-3 carboxylic acid or corn oil placebo, with a primary endpoint of cardiovascular death, myocardial infraction, stroke, coronary revascularization or hospitalization for unstable angina. The trial was stopped early due to “futility,” though it still achieved 1580 of the target 1600 endpoints needed for results to be sufficiently powered. Compared with those receiving corn oil placebo, participants in the omega-3 fatty acid group experienced a 19% reduction in triglycerides, 20% reduction in C-reactive protein and 269% increase in plasma eicosapentanoic acid (EPA; icosapent ethyl is a highly purified and stable version of this fatty acid). Despite these biochemical differences, there was no difference in the primary outcome between the two groups, 54 months after randomization. The major adverse outcome, atrial fibrillation, was significantly more likely in the treatment arm.
Why do STRENGTH findings differ from those of REDUCE-IT? STRENGTH and REDUCE-IT participants had similar triglyceride levels, but patients in the STRENGTH intervention arm had lower EPA levels than those in the REDUCE-IT treatment arm. Moreover, REDUCE-IT contained more participants with established CAD. Additionally, STRENGTH used a corn oil placebo, while REDUCE-IT used a mineral oil placebo. Corn oil has been shown to have a neutral effect on triglycerides and potentially some cardioprotective effects, while mineral oil may result in unfavorable increases in triglycerides and LDL. Some may argue that the use of mineral oil in REDUCE-IT might have exaggerated the efficacy of icosapent ethyl.
The OMEMI trial, meanwhile, randomized 1,000 elderly, 70-82 year old patients (who had had a myocardial infarction [MI] in the 2-8 weeks prior to enrollment) to 1.8 grams of omega-3 fatty acids or a matching corn oil placebo for 2 years. It excluded participants who could not tolerate fatty acids or who had diseases that would impact their ability to survive the 2 year study period. OMEMI found no difference in the composite primary outcome (non-fatal MI, unscheduled revascularization, stroke, hospitalization for heart failure or all-cause death). There were no significant differences in key clinical subgroup analyses, and there was a greater (though not statistically significant) risk of atrial fibrillation in the treatment arm. There was no difference in major bleeding.
Taken together, findings from STRENGTH and OMEMI complicate the picture of fish oil utilization and raise further questions about whether the cardiovascular effects of fish oils in some populations are beneficial or neutral. More work needs to be done to better elucidate the effects of fish oils on cardiovascular risk reduction in high-risk patients.
Nevertheless, while STRENGTH and OMEMI made waves owing to their potential practice-changing implications, I left the day feeling particularly inspired by the SAMSON trial. This ingeniously designed trial enrolled 60 participants who had stopped taking statins due to symptoms arising within two weeks. Any symptom was eligible if it was severe enough to lead to statin discontinuation in that time span. The most common symptoms were muscle aches, fatigue, and cramps. Participants were given four bottles containing atorvastatin 10 mg tablets, four bottles containing placebo pills and four empty bottles. Each month, they were randomly assigned to take the contents of one of the bottles, in a crossover fashion, with no washout between months. They were asked to rate the severity symptoms they experienced using a mobile phone app. They were also asked 6 months after the conclusion of the trial if they had resumed taking statins. Investigators combined symptom ratings, reporting average symptoms levels during “statin”, “placebo” and “no treatment” months.
SAMSON found that the severity of symptoms reported was substantially higher during statin months than during no treatment months; however, this was also true for placebo. Reported symptom levels during statin and placebo months were no different from each other. The nocebo proportion was 0.9; that is, 90% of symptoms reported during statin months were elicited by taking placebo tablets as well. Even more importantly, half of the participants resumed statins again after the trial!
SAMSON serves as a lesson to aspiring cardiovascular researchers that even a small study can have a major impact. It displays respect and empathy for the patient experience by acknowledging rather than denying that patients do experience side effects from statins. However, it also strongly suggests that these symptoms may be attributable to the act of taking a pill rather than the medication content of the pill itself. Lastly, SAMSON proves that patients who realize that statin side effects may not actually be specific to statins themselves may be willing to resume taking statins. These findings further support the foundational concept that we as physicians must respect our patients by engaging them in shared decision-making and give patients an opportunity to understand the science, rather than simply telling them what to do.
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Andi Shahu is a first-year Cardiology fellow at Yale-New Haven Hospital in New Haven, CT and a recent graduate of the Osler Medical Residency at Johns Hopkins Hospital. He is interested in the intersection between cardiovascular outcomes, health equity, and health policy. He is a member of the Council On Quality of Care and Outcomes Research (QCOR). He also loves traveling, writing, music and running. You can follow him on Twitter @andishahu.